DARU Journal of Pharmaceutical Sciences
Year:2013 | Volume:21 | Issue:9|Papers Count:12

Dear Editor-in-Chief: Recently much attention has been directed toward kidney protective property of erythropoietin (EPO) beyond stimulating erythropoiesis. In the study conducted by Moieni et al. the protective inpact of recombinant human erythropoietin in kidney and lung injury following renal bilateral ischemia-reperfusion (I/R) in rat model was investigated. They studied the role of EPO on renal function makers and tissue damage as well as the lung endothelial permeability in bilateral renal ischemia/reperfusion (I/R) injury model in rats. In this study they found that EPO protected the kidney against I/R injury. Likewise to this study, Ardalan et al.

Ethidium bromide (EtBr) is a well-known fluorescent tag usually applied in molecular biological techniques like agarose gel electrophoresis. The mechanism of action for such compounds is known, in which these compounds are able to bind to the kinetoplastid DNA and to alter their conformation to Z-DNA molecules that stop replication of kinetoplastid DNA leading to Trypanosoma death. Although the usual amounts used in laboratories are considered as below the level required to cause toxicity (LD50 in oral administration in rat is 1.5 g/Kg), the mentioned concentrations are high enough to involve in replication of mitochondrial DNA in some human cell lines. Regarding the points that EtBr is very stable in the environment and if degraded especially by use of bleaches that result in formation of mutagenic compounds, there is a big concern about its use. Although application of EtBr is going to be restricted and replaced with other tags such as SYBRÒ products, the safety of the new substituted compounds are still in doubt and except a few data, there is no essential evidence available to confirm that they are safer than EtBr. Further investigations are recommended to compare their relative biosafety hazards.

Background and the purpose of the study: Modafinil, a novel wake-promoting agent with low potential for abuse and dependence, has a reliable structure to find some novel derivatives with better activity and lower potential for abuse and risk of dependency. This study was designed to evaluate psychobiological activity of some novel N-aryl modafinil derivatives.Methods: Seven novel N-aryl modafinil derivatives were synthesized through three reactions: a) preparation of benzhydrylsulfanyl acetic acid through reaction of benzhydrol with thioglycolic acid, b) formation of desired amide by adding the substituted aniline to activated acid with EDC (1-ethyl-3- (3-dimethyl amino propyl) carbodiimide). This reaction was catalyzed by HOBt (N- hydroxylbenzotriazole), and c) oxidation of sulfur to sulfoxide group with H2O2.Then, their psychobiological effect on the performance of male albino mice were compared to that of modafinil as following: wakefulness by determining the effects of derivatives on phenobarbital-induced loss of the righting reflex (LOPR); exploratory activity by measuring activity in the open field test (OFT); depression by measuring immobility time (IT) during forced swimming test (FST) and the anxiogenic and anxiolytic like effects by using elevated plus-maze test (EPM). All tests were videotaped and analyzed for the frequency and duration of the behaviors during the procedures.Conclusions: 2- (Benzhydrylsulfonyl) -N- (4-chlorophenyl) acetamide (4c) showed comparable result in LOPR test.However, all analogs were found to be stimulant except 2- (benzhydrylsulfinyl) -N-phenylacetamide (4a). Also 4c led the most exploratory activity in mice among derivatives. FST results showed that 4a had the longest IT while modafinil, 2- (benzhydrylsulfinyl) -N- (3-chlorophenyl) acetamide (4b) and 2- (benzhydrylsulfinyl) -N- (4-ethylphenyl) acetamide (4d) had the shortest IT. In EPM, all derivatives showed anxiogenic-like behavior since they decreased open arms time and open arms entries and simultaneously increased close arms time.

Background: Cyclodextrins (CDs) have been shown to improve physicochemical and biopharmaceutical properties of drugs when low solubility and low safety limit their use in the pharmaceutical field. Recently, a new amphiphilic peptide-substituted- b -CD, hepta- (N-acetyl-Leu-Gly-Leu) - b-CD (hepta- (N-acetyl-LGL) - b -CD), is developed which exhibited good solubility, strong inclusion ability and an appropriate average molecular weight.However, there is limited information available about its toxic effects. This study was designed to evaluate cytotoxic effects of the hepta- (N-acetyl-LGL) - b-CD (50, 200, 400, and 800 m g/ml) on rat pheochromocytoma PC-12 cells.Results: A significant reduction of cell viability with IC50 values of 1115.0 m/ml, 762.4 m g/ml, and 464.9 m g/ml at 6, 12, and 24 h post-treatment, respectively, as well as increased lipid peroxide levels and DNA damage were observed.Conclusions: In conclusion, hepta- (N-acetyl-Leu-Gly-Leu) - b-CD exhibit significant toxic properties at high concentrations, probably through induction of oxidative stress and genotoxicity.

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Introduction: Supply of medicine as a strategic product in any health system is a top priority. Pharmaceutical companies, a major player of the drug supply chain, are subject to many risks. These risks disrupt the supply of medicine in many ways such as their quantity and quality and their delivery to the right place and customers and at the right time. Therefore risk identification in the supply process of pharmaceutical companies and mitigate them is highly recommended.Objective: In this study it is attempted to investigate pharmaceutical supply chain risks with perspective of manufacturing companies.Methods: Scopus, PubMed, Web of Science bibliographic databases and Google scholar scientific search engines were searched for pharmaceutical supply chain risk management studies with 6 different groups of keywords. All results found by keywords were reviewed and none-relevant articles were excluded by outcome of interests and researcher boundaries of study within 4 steps and through a systematic method.Results: Nine articles were included in the systematic review and totally 50 main risks based on study outcome of interest extracted which classified in 7 categories. Most of reported risks were related to supply and supplier issues.Organization and strategy issues, financial, logistic, political, market and regulatory issues were in next level of importance.Conclusion: It was shown that the majority of risks in pharmaceutical supply chain were internal risks due to processes, people and functions mismanagement which could be managed by suitable mitigation strategies.

Background and the aim of the study: The objective of the present study was to formulate and optimize nanoparticles (NPs) of sildenafil-loaded poly (lactic-co-glycolic acid) (PLGA) by double emulsion solvent evaporation (DESE) method. The relationship between design factors and experimental data was evaluated using response surface methodology.Method: A Box-Behnken design was made considering the mass ratio of drug to polymer (D/P), the volumetric proportion of the water to oil phase (W/O) and the concentration of polyvinyl alcohol (PVA) as the independent agents. PLGA-NPs were successfully prepared and the size (nm), entrapment efficiency (EE), drug loading (DL) and cumulative release of drug from NPs post 1 and 8 hrs were assessed as the responses.Results: The NPs were prepared in a spherical shape and the sizes range of 240 to 316 nm. The polydispersity index of size was lower than 0.5 and the EE (%) and DL (%) varied between 14-62% and 2-6%, respectively. The optimized formulation with a desirability factor of 0.9 was selected and characterized. This formulation demonstrated the particle size of 270 nm, EE of 55%, DL of 3.9% and cumulative drug release of 79% after 12 hrs. In vitro release studies showed a burst release at the initial stage followed by a sustained release of sildenafil from NPs up to 12 hrs.The release kinetic of the optimized formulation was fitted to Higuchi model.Conclusions: Sildenafil citrate NPs with small particle size, lipophilic feature, high entrapment efficiency and good loading capacity is produced by this method. Characterization of optimum formulation, provided by an evaluation of experimental data, showed no significant difference between calculated and measured data.

Background and the purpose of the study: Several 2, 4-dinitrophenyl and 2, 4-dinitrophenylamine tethered 5-FU (5-fluorouracil) compared to their components have shown minimal or no cytotoxicity to HT-29 cell line under aerobic conditions but high cytotoxicity and radiosensitizing effects under hypoxic conditions. In the present study the cytotoxicity and radiation potentiation of three novel analogues of these compounds by replacing 2, 4-dinitrophenyl moiety with 2-methyl-5-nitroimidazole, a known radiosensitizer and cytotoxic agent was investigated.Methods: Tethered compounds 7–9 were prepared by the reaction of 1- (t-butoxycarbonyl) -5-fluorouracil 6 with metronidazole esters 2–4 followed by removal of the t-butoxycarbonyl protecting group. Cytotoxicity of compounds in HT-29 cells with or without radiation were determined by 3- (4, 5-Dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT), propidium iodide (PI) -digitonin and clonogenic assays.Results: Tethered compounds 7-9 induced time-and concentration–dependent cytotoxicity under hypoxia but had no significant effect under aerobic conditions. These compounds also showed selective and concentration- dependent radiosensitization effects under hypoxic conditions.Conclusion: Tethered compounds 7-9 compared to 5-FU 5 showed minimal cytotoxicities under aerobic and selective radiosensitizing activities under hypoxic conditions. Also effects of these compounds were higher than those of metronidazole 1 which is a known cytotoxin and radiosensitizer under hypoxic conditions.

Zolpidem is a popular drug indicated for the short-term treatment of insomnia. Side effects are not uncommon with zolpidem. Herein we describe an Iranian 27-year-old man with no known mood disorder or neuropsychological disease who attempted suicide upon taking zolpidem. There are two interesting facts about this case: Firstly, the patient had not history of suicide attempt or thinking. Secondly, this case had experienced suicide ideation after taking 20 mg of zolpidem, suggesting a possible correlation between zolpidem psychological effects and dangerous psychological behaviors.

Background: Berberine was encapsulated in yeast cells of Saccharomyces cerevisiae as novel carriers to be used in different food and drug industries. The microcapsules were characterized by differential scanning calorimetry (DSC), fourier transform infra red spectroscopy (FT-IR) and fluorescence microscopy. The encapsulation factors such as plasmolysis of yeast cells which affects the % encapsulation yield were studied.Results: Fluorescence microscopy showed the yeast cells became fluorescent after encapsulation process. DSC diagram was representing of new peak for microcapsule which was not the same as berberine and the empty yeast cells peaks, separately. FTIR spectrums of microcapsules and yeast cells were almost the same. The plasmolysed and non plasmolysed microcapsules were loaded with berberine up to about 40.2±0.2% w/w.Conclusion: Analytical methods proved that berberine was encapsulated in the yeast cells. Fluorescence microscopy and FTIR results showed the entrance of berberine inside the yeasts. DSC diagram indicated the appearance of new peak which is due to the synthesis of new product. Although plasmolysis caused changes in yeast cell structure and properties, it did not enhance berberine loading in the cells. The results confirmed that Saccharomyces cerevisiae could be an efficient and safe carrier for active materials.

Background and the purpose of the study: A common approach in cancer chemotherapy is development of drugs that interrupt the mitosis phase of cell division. Dimethylenastron is a known kinesin inhibitor. In this study, six novel dimethylenastron analogues (4a-f), in which 3-hydroxyphenyl substituent has been replaced with substituted benzylimidazolyl, were synthesized through Biginelli reaction.Methods: Six novel Biginelli compounds (4a-f) were synthesized through one step Biginelli reaction of imidazole aldehydes (3a-c), dimedone and urea or thioura. In vitro cytotoxicities of prepared compounds were investigated using MTT assay. Furthermore the ELIPA kit was implemented to study inhibitory effects of synthesized compounds on ATPase activity of kinesin by measuring of organic phosphate.Results: Our results indicated that analogue 4c is the most toxic and analogues 4f, 4b and dimethylenasteron were less cytotoxic in compare with other analogues. On the other hand, analogue 4a, 4b, 4c and 4e showed stronger Kinesin inhibition as compared with analogue 4f and dimethylenasteron. None of synthesized compounds were as potent kinesin inhibitor as Taxol. Docking analysis revealed that hydrogen bond formation and hydrophobic interactions were the key factors affecting inhibitory effects of these compounds.Conclusion: Newly synthesized compounds were found to have moderate to good cytotoxicity against HeLa cancer cell. Our results may be helpful in further design of dihydropyrimidine as potential anticancer agents.

Background: Natural compounds can be alternative sources for finding new lead anti-cancer molecules. Marine algae have been a traditional source for bioactive compounds. Enteromorpha intestinalis and Rhizoclonium riparium are two well distributed saline/brackish water algae from Sundarbans. There’s no previous report of these two for their anti-proliferative activities.Methods: Cytotoxicity of the algal methanolic extracts (AMEs) on HeLa cells were assayed by 3- (4, 5-dimethylthiazol-2-yl) -2, 5- diphenyltetrazolium bromide (MTT) reduction assay. Morphological examinations were done by Haematoxylin, Hoechst 33258 and Acridine orange staining. DNA fragmentation was checked. Gene expressions of Cysteine aspartate protease (Caspase) 3, Tumor protein (TP) 53, Bcl-2 associated protein X (Bax) were studied by Reverse transcription- polymerase chain reaction (RT-PCR) keeping Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as internal control. Protein expressions were studied for Caspase 3, phospho-p53, Bax, Microtubule associated proteins-1/ light chain B (MAP1/LC3B) by western blot.Results: The AMEs were found to be cytotoxic with Inhibitory concentration 50 (IC50) values 309.048±3.083 mg/ml and 506.081±3.714 mg/ml for E. intestinalis and R. riparium extracts respectively. Treated cells became round with blebbings with condensed nuclei. Acidic lysosomal vacuoles formation occurred in treated cells. Expression of apoptotic genes in both mRNA and protein level was lowered. Expression of LC3B-II suggested occurrence of autophagy in treated cells.Conclusions: These two algae can be potent candidates for isolating new lead anticancer molecules. So they need further characterization at both molecular and structural levels.